Uterus Transplantation: A 50-Year Journey.

This paper provides an analysis of the last 50 years of uterus transplantation (UTx). Animal research on UTx began in the 1960s, aiming to solve tubal factor infertility. The success of in vitro fertilization shifted the focus onto uterine factor infertility. Early research in small and large animals improved following the advent of immunosuppression and established the uterus' ability to tolerate cold ischemia and to function following vessel reanastamosis. Upon the achievement of the first live birth following UTx in 2014, human research has started to focus on reducing donor morbidity, optimal immunosuppression regimes, and the development of deceased donor UTx programmes.

Uterine Transplantation in 2021: Recent Developments and the Future.

Uterine transplantation has evolved rapidly over the last decade. As the number of cases performed increases exponentially worldwide, emerging evidence continues to improve collective knowledge and understanding of the procedure, with the aim of improving both surgical and reproductive outcomes. Although currently restricted to women with absolute uterine factor infertility, increasing awareness as a method of fertility restoration has resulted in a demand for the procedure to be undertaken in transgender women. This manuscript summarizes the recent advances in uterine transplantation, and elaborates further upon the key novel avenues research within the field will focus on over the coming years.

The application of metabolomics in ovarian cancer management: a systematic review.

Metabolomics, the global analysis of metabolites in a biological specimen, could potentially provide a fast method of biomarker identification for ovarian cancer. This systematic review aims to examine findings from studies that apply metabolomics to the diagnosis, prognosis, treatment, and recurrence of ovarian cancer. A systematic search of English language publications was conducted on PubMed, Science Direct, and SciFinder. It was augmented by a snowball strategy, whereby further relevant studies are identified from reference lists of included studies. Studies in humans with ovarian cancer which focus on metabolomics of biofluids and tumor tissue were included. No restriction was placed on the time of publication. A separate review of targeted metabolomic studies was conducted for completion. Qualitative data were summarized in a comprehensive table. The studies were assessed for quality and risk of bias using the ROBINS-I tool. 32 global studies were included in the main systematic review. Most studies applied metabolomics to diagnosing ovarian cancer, within which the most frequently reported metabolite changes were a down-regulation of phospholipids and amino acids: histidine, citrulline, alanine, and methionine. Dysregulated phospholipid metabolism was also reported in the separately reviewed 18 targeted studies. Generally, combinations of more than one significant metabolite as a panel, in different studies, achieved a higher sensitivity and specificity for diagnosis than a single metabolite; for example, combinations of different phospholipids. Widespread metabolite differences were observed in studies examining prognosis, treatment, and recurrence, and limited conclusions could be drawn. Cellular processes of proliferation and invasion may be reflected in metabolic changes present in poor prognosis and recurrence. For example, lower levels of lysine, with increased cell invasion as an underlying mechanism, or glutamine dependency of rapidly proliferating cancer cells. In conclusion, this review highlights potential metabolites and biochemical pathways which may aid the clinical care of ovarian cancer if further validated.

A Unique Case of Extraovarian Sex-Cord Stromal Fibrosarcoma, With Subsequent Relapse of Differentiated Sex-Cord Tumor.

Primary fibrosarcoma arising from ovarian sex-cord stroma is a very rare neoplasm, with only a few reports in the literature. These tumors have been reported to express inhibin which allows their distinction from fibrosarcomas of soft tissue. Here, we report a case of a fibrosarcoma arising in the broad ligament. Despite being totally separate from the ovary, the tumor was diagnosed as sex-cord stromal type on the basis of inhibin expression. Furthermore, this patient suffered a recurrence of her tumor in the pelvis, which showed both the fibrosarcomatous, as well as other sex-cord elements, confirming the sex-cord stromal differentiation of the sarcoma. To our knowledge, this is the first case of a sex-cord stromal fibrosarcoma arising from an extraovarian site. Furthermore, this is also the first case of a recurrent fibrosarcoma, which showed redifferentiation of the tumor into other sex-cord components.

Achieving uterine auto-transplantation in a sheep model using iliac vessel anastomosis: a short-term viability study.

OBJECTIVE: To investigate, develop and evaluate anatomical, surgical and anastomotic aspects necessary for a successful uterine transplant in a large-animal model. DESIGN: Sheep model; longitudinal study involving five ewes. SETTING: Royal Veterinary College, London, UK. POPULATION: Five ewes of proven fertility. METHODS: The uterine allograft along with the internal iliacs, and uterine arterial and venous tree all intact were harvested en bloc. An end-to-side anastomosis was performed between the external iliac vessels and the internal iliac vessels of the graft using 6-0 polypropylene. Successful reperfusion of the graft was initially judged by the color shift of the uterus during reperfusion. Blood flow past the venous and arterial anastomotic sites was also ensured by visual inspection, together with pulse oximetry and multispectral imaging. MAIN OUTCOME MEASURES: Operative details (retrieval, ischemic, clamping, reperfusion and recipient hysterectomy duration); physiological profiles; gross morphology and histopathology. RESULTS: Five autotransplants were performed. One procedure was abandoned because of the inappropriate size of sheep model. Another procedure was halted because the animal suffered from respiratory failure in the immediate intra-operative period. Three transplants were completed. In those, at least two of four possible anastomoses were finished and the grafted uteri demonstrated immediate perfusion and appropriate viability 45 min post-operatively. CONCLUSIONS: Internal to external iliac vessel anastomoses are an acceptable surgical technique that should be applied in a human model to ensure adequate subsequent uterine perfusion.

Is there a role for transplantation in gynecologic oncology? Autotransplantation and other lessons.

We describe an exciting and novel surgical option, which may be used to treat formerly unresectable masses. This process is commonly referred to as autotransplantation (AuTn), and it combines the advances in transplant medicine and applies them to surgical oncology. The idea behind AuTn is the removal of the cancerous organ(s) to allow complete anatomic resection of the tumor mass, with consequent anastomotic reimplantation or AuTn of the now macroscopically tumor-free organ back into the patient. Autotransplantation has been used to remove large fibromatosis and desmoid tumors as well as malignant tumors. Our belief is that using lessons learned from the field of transplantation, AuTn can be applied in gynecologic oncology.

The Clinical Application of Platelet-Rich Plasma in the Female Reproductive System: A Narrative Review.

Platelet-rich plasma is an autologous plasma containing platelets prepared from fresh whole blood drawn from a peripheral vein. Through processing, it can be prepared to contain supraphysiologic levels of platelets at three to five times greater than the level of normal plasma. PRP has been explored both in vivo and ex vivo in the human endometrium model in its ability to harness the intrinsic regenerative capacity of the endometrium. Intrauterine autologous PRP infusions have been shown to increase endometrial thickness and reduce the rate of intrauterine adhesions. In the setting of recurrent implantation failure, intrauterine infusion of PRP has been shown to increase clinical pregnancy rate. PRP also appears to hold a potential role in select patients with premature ovarian insufficiency, poor ovarian responders and in improving outcomes following frozen-thawed transplantation of autologous ovarian tissue. Further studies are required to explore the potential role of PRP in reproductive medicine further, to help standardise PRP protocols and evaluate which routes of administration are most effective.

INvestigational Study Into Transplantation of the Uterus (INSITU): a cross-sectional survey among women with uterine factor infertility in the UK assessing background, motivations and suitability.

IMPORTANCE: The study summarises the selection prescreen criteria currently used in the UK for a uterus transplant and highlights the number of women who are suitable to proceed. OBJECTIVES: To assess the demographics, motivations, reasons and suitability among women with absolute uterine factor infertility (AUFI) to undergo uterine transplantation (UTx). DESIGN: A cross-sectional survey. SETTING: An electronic questionnaire was sent via email to women with AUFI who had previously been referred to the UTx research team or approached the Womb Transplant UK Charity. The questions assessed suitability to undergo UTx based on demographic information, perceptions to adoption and surrogacy and reasons why UTx was preferable. Responses were assessed against the study selection criteria. PARTICIPANTS: Women with AUFI. RESULTS: 210 women completed the questionnaire. The most common aetiology of AUFI in our cohort was Mayer-Rokitansky-Küster-Hauser (68%; n=143) whereas 29% (n=62) had previously undergone hysterectomy. 63% (n=132) of the cohort had previously considered adoption, 5% (n=11) had attempted it and 2 (1%) had successfully adopted. The most common reason cited to undergo UTx over adoption was to experience gestation (n=63; 53%), while 37% (n=44) wanted a biologically related child. 76% (n=160) of participants had previously considered surrogacy, 22 (10%) had attempted it and 2 (1%) had successfully become mothers using a surrogate. The most common reason to undergo UTx over surrogacy was to experience gestation (n=77; 54%). 15% (n=21) were concerned about the legal implications, 14% (n=20) identified the financial cost as a barrier and 8% (n=12) could not consider it due to religious reasons. On adhering to the selection criteria, 65 (31%) women were suitable to proceed with the trial. CONCLUSION: The study demonstrates that implementing commonly used selection criteria for a UTx led to an attrition rate of more than two-thirds of women who requested to initially undergo the process. As more studies present outcomes following UTx, critical assessment of the selection criteria currently used is warranted to ensure potential recipients are not being unnecessarily excluded. TRIAL REGISTRATION NUMBER: NCT02388802.

Orthoplastic management of open tibial fractures in children : a consecutive five-year series from a paediatric major trauma centre.

AIMS: Open tibial fractures are limb-threatening injuries. While limb loss is rare in children, deep infection and nonunion rates of up to 15% and 8% are reported, respectively. We manage these injuries in a similar manner to those in adults, with a combined orthoplastic approach, often involving the use of vascularised free flaps. We report the orthopaedic and plastic surgical outcomes of a consecutive series of patients over a five-year period, which includes the largest cohort of free flaps for trauma in children to date. METHODS: Data were extracted from medical records and databases for patients with an open tibial fracture aged < 16 years who presented between 1 May 2014 and 30 April 2019. Patients who were transferred from elsewhere were excluded, yielding 44 open fractures in 43 patients, with a minimum follow-up of one year. Management was reviewed from the time of injury to discharge. Primary outcome measures were the rate of deep infection, time to union, and the Modified Enneking score. RESULTS: The mean age of the patients was 9.9 years (2.8 to 15.8), and 28 were male (64%). A total of 30 fractures (68%) involved a motor vehicle collision, and 34 (77%) were classified as Gustilo Anderson (GA) grade 3B. There were 17 (50%) GA grade 3B fractures, which were treated with a definitive hexapod fixator, and 33 fractures (75%) were treated with a free flap, of which 30 (91%) were scapular/parascapular or anterolateral thigh (ALT) flaps. All fractures united at a median of 12.3 weeks (interquartile range (IQR) 9.6 to 18.1), with increasing age being significantly associated with a longer time to union (p = 0.005). There were no deep infections, one superficial wound infection, and the use of 20 fixators (20%) was associated with a pin site infection. The median Enneking score was 90% (IQR 87.5% to 95%). Three patients had a bony complication requiring further surgery. There were no flap failures, and eight patients underwent further plastic surgery. CONCLUSION: The timely and comprehensive orthoplastic care of open tibial fractures in this series of patiemts aged < 16 years resulted in 100% union and 0% deep infection, with excellent patient-reported functional outcomes. Cite this article: Bone Joint J 2021;103-B(6):1160-1167.

Why do patients not kneel after total knee replacement? Is neuropathic pain a contributing factor?

AIMS: Despite kneeling being an important and valued function of the knee, a proportion of patients are unable to kneel following arthroplasty. We explore the reasons for this, and assess whether neuropathic pain is a contributing factor. METHODS: In this observational study, data was collected prospectively for 134 knees. At one year follow-up, patients completed a semi-structured questionnaire, the Oxford Knee Score (OKS), and the painDETECT score. Ability to kneel was assessed by question 7 of the OKS. Change in kneeling ability was assessed using Wilcoxon signed-rank test, normal data with independent t-test, and a regression and ANOVA analysis performed to assess predictors of kneeling ability. RESULTS: 88% of patients had tried kneeling post-operatively. There was no change in kneeling ability for the whole cohort from pre- to post-operatively (p = 0.313). Patient reasons for not kneeling varied. Male gender, younger age and a reduced pain score were all significantly associated with a greater ability to kneel postoperatively. There was a trend towards an improved ability with increased flexion. Mean pain scores for all kneeling abilities lay within the nociceptive rather than neuropathic range. CONCLUSION: Kneeling ability varies greatly post-knee replacement, and is multifactorial. Greater pain is a contributing factor to the inability to kneel postoperatively, but this appears to be nociceptive rather than neuropathic in nature.

Use of Laser Speckle Contrast Analysis during pelvic surgery in a uterine transplantation model.

AIM: Uterine transplantation (UTx) is proposed for treatment of uterine factor infertility. Our aim was to assess whether Endoscopic Laser Speckle Contrast Analysis (eLASCA) could evaluate pelvic blood flow at anastomotic sites required for sheep and rabbit UTx. RESULTS/METHODOLOGY: eLASCA detected blood flow in rabbit UTx #7 and #9. In sheep UTx #2, #3 and #5, the results allowed us to conclude that blood flow was present in the uterine graft following transplantation; and post-UTx, the animal had heart and respiratory rates, and oxygen saturation compatible with a normal hemodynamic status. CONCLUSION: These preliminary results establish the potential of Laser Speckle Contrast Analysis as noncontact and real-time tool for observation of spatially-resolved blood flow from which other parameters can be derived.

Use of biomedical photonics in gynecological surgery: a uterine transplantation model.

AIM: Uterine transplantation (UTx) has been proposed as a treatment for permanent absolute uterine factor infertility. The study aims were to compare pulse oximetry and multispectral imaging (MSI), for intraoperative tracking of uterine oxygen saturation in animal UTx models (rabbit and sheep). RESULTS/METHODOLOGY: Imaging results confirmed the re-establishment of adequate perfusion in the transplanted organ after surgery. Comparison of oxygen saturation values between the pre-UTx donor and post-UTx recipient, and pre-UTx and post-UTx recipient reveals a statistically significant decrease in saturation levels post-UTx. CONCLUSION: The use of MSI is the first case in gynecology and has demonstrated promise of possible future human use. MSI technique has advantages over pulse oximetry - it provides spatial information in a real-time, noncontact manner.

Gynecological cancers: an alternative approach to healing.

Grief and hope are two conflicting emotions that a patient recently diagnosed with cancer has to master. The real challenge for gynecologic oncologists is how to reach out. Conventional wisdom states that offering patients focus and belief when combating cancer in their lives allows them to embrace hope with greater confidence, which minimizes their grief. Three pictorial models are presented: '4-cusp approach' model used at the initial consultation; 'tapestry of bereavement or landscape of grief' model at the postsurgery consultation; and 'Venn-diagram' model at any time during patient management. We have applied these models in our practice and believe that they can act as a fulcrum for the patient, the family and healthcare team around which therapy should be centered.

Multispectral imaging of organ viability during uterine transplantation surgery in rabbits and sheep.

Uterine transplantation surgery (UTx) has been proposed as a treatment for permanent absolute uterine factor infertility (AUFI) in the case of the congenital absence or surgical removal of the uterus. Successful surgical attachment of the organ and its associated vasculature is essential for the organ's reperfusion and long-term viability. Spectral imaging techniques have demonstrated the potential for the measurement of hemodynamics in medical applications. These involve the measurement of reflectance spectra by acquiring images of the tissue in different wavebands. Measures of tissue constituents at each pixel can then be extracted from these spectra through modeling of the light­tissue interaction. A multispectral imaging (MSI) laparoscope was used in sheep and rabbit UTx models to study short- and long-term changes in oxygen saturation following surgery. The whole organ was imaged in the donor and recipient animals in parallel with point measurements from a pulse oximeter. Imaging results confirmed the re-establishment of adequate perfusion in the transplanted organ after surgery. Cornual oxygenation trends measured with MSI are consistent with pulse oximeter readings, showing decreased StO2 immediately after anastomosis of the blood vessels. Long-term results show recovery of StO2 to preoperative levels.